吸入性一氧化氮治療發生腎衰竭風險之研究:臨床試驗統合分析及世代研究之證據

Abstract

背景: 吸入性一氧化氮(Inhaled nitric oxide)是一種血管擴張藥物，可選擇性擴張肺部血管，而不會影響周邊血管造成低血壓，臨床上被用於急性呼吸窘迫症候群(Acute respiratory distress syndrome)、及肺血管高壓相關疾病的治療。過去的研究顯示，吸入性一氧化氮具有很好的藥物安全性。但有零星的資料顯示，一氧化氮治療可能會帶來腎損傷風險，然而未有定論。因此，我們欲利用統合分析的方法，分析已發表的隨機臨床試驗，以評估一氧化氮治療是否會升高腎損傷之風險，並利用觀察性研究，評估該風險在一般臨床情境中之高低，以及該風險與病人之背景腎功能和疾病嚴重度之間的交互作用。 方法: 首先，我們以系統性文獻回顧及統合分析的方法，找出已發表的隨機臨床試驗，進行評估吸入性一氧化氮與腎損傷風險之間的關係。統合分析之主要方法是採用隨機效應模型(Random-effects model)。在敏感性分析中，我們亦使用不同的統合分析模型，來了解不同分析方法對風險估計的影響。研究的第二部分，我們利用台灣一醫學中心的資料，來進行世代研究，評估一氧化氮所帶來的腎損傷導致血液透析的風險，是否與統合分析所觀察到的風險大小一致，並評估該風險與病人之背景腎功能和疾病嚴重度之間有無交互作用。我們利用傾向分數(Propensity score)配對、及競爭風險分析(Competing-risks analysis)的方法，來進行資料的分析。 結果: 研究的第一部分，經由系統性文獻回顧共找出10個隨機臨床試驗，包含了1363位受試者。其中有4個臨床試驗(919位受試者)是屬於急性呼吸窘迫症候群，另6個研究受試者是肺高壓及其他族群。統合分析的結果顯示，吸入性一氧化氮的治療顯著地增加腎損傷的風險(相對風險1.4倍, 95%信賴區間: 1.06-1.83)，尤其是在急性呼吸窘迫症候群的病人中風險更高(相對風險1.55倍, 95%信賴區間: 1.15-2.09)。第二部份的世代研究納入了547位急性呼吸窘迫症候群的病人，其中包含216位吸入性一氧化氮使用者。吸入性一氧化氮引起腎衰竭的未調整風險比值為2.23倍(95%信賴區間: 1.61-3.09)，經傾向分數配對及競爭風險分析之計算後，調整後之風險比值為1.59倍(95%信賴區間: 1.08-2.34)，年齡對於此風險有修飾作用(p-value for interaction = 0.05)，年齡大於65歲者，更易遭受吸入性一氧化氮所引起腎衰竭之危害。 結論: 我們的研究結果顯示，吸入性一氧化氮會升高急性呼吸窘迫症候群病人發生腎衰竭的風險，尤其在老年患者此風險會更加升高。臨床上若使用吸入性一氧化氮治療病人時，建議應規則監測腎功能，以即時發現腎功能之變化而能做出適當的處置。將來吸入性一氧化氮相關之臨床試驗，亦應注意此一藥物安全議題。

Background: Inhaled nitric oxide (iNO) possesses the therapeutic effects of selective pulmonary vasodilatation without causing systemic hypotension and is a therapy for acute respiratory distress syndrome (ARDS) and pulmonary arterial hypertension. Previous studies suggest that iNO therapy has a good safety profile and its potential adverse effects are usually mild. However, safety concerns regarding iNO and renal dysfunction have been reported but remains controversial. Our objectives were using the data from published randomized controlled trials (RCTs) to ascertain the risk of renal dysfunction associated with iNO therapy and to evaluate the risk magnitude in real-world practice by a cohort study. Methods: Firstly, we conduct a systematic review of randomized trials to evaluate the risk of renal dysfunction associated with iNO therapy. Effect estimates for risk ratio of renal dysfunction were pooled using a random-effects model with the DerSimonian and Laird method. Sensitivity analysis by different data synthesis models was performed to check the robustness of the effect estimate. Secondly, we conducted a hospital-based cohort study to evaluate the risk of iNO-associated renal dysfunction in real-world practice. Propensity score matching and competing-risks analysis were used for data analysis. We also explore the effect modification by age, baseline renal function and disease severity. Results: Through the systematic review, 10 RCTs involving a total of 1363 patients were identified. The study population was ARDS in 4 trials (919 subjects) and pulmonary hypertension and other diseases in 6 trials. Meta-analysis showed that iNO therapy significantly increased the risk of renal dysfunction (Risk ratio = 1.4, 95%CI, 1.06-1.83), especially in patients with ARDS (Risk ratio = 1.55, 95%CI, 1.15 to 2.09). In addition, the cohort study enrolled 547 patients with ARDS, including 216 iNO users. The crude hazard ratio of renal failure requiring renal replacement therapy in iNO-users compared with non-users was 2.23 (95% CI, 1.61-3.09). After propensity score matching and competing-risks analysis, the adjusted hazard ratio was 1.59 (95% CI, 1.08-2.34). Older aged patients (≥65 years) were more susceptible to iNO-associated kidney injury than younger patients (p-value for interaction = 0.05). Conclusions: Our findings suggest that iNO therapy substantially increased the risk of renal dysfunction in patients with ARDS. Older aged patients were especially susceptible to this adverse event. We suggest that renal function should be monitored during iNO therapy and that future clinical trials of iNO should evaluate renal safety.